Biochemistry



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Misoprostol


-PGE1 analogue which is cytoprotective

-Increase bicarb and mucous secretion

-GI symptom relief

-Selective NSAID induced GI ulcers

Sucralfate

-Polymerizes and forms a protective gel like coating of ulcer beds

-Will increase healing

-Decrease ulcer recurrence

-need acid pH antacids interfere

-May decreases oral absorption of drugs like azoles, f-quinolones, tcns

Antacid drugs

-Aluminum Hydroxide

-Calcium Carbonate

-Magnesium Hydroxide

-Sodium Bicarbonate

-Neutralization of protons in the stomach

-ALOH: constipation

-CACO3: acid rebound, constipation

-MGOH:acid rebound, diarrhea

-NAHCO3: Alkalosis

-Some toxicities associated with antacids:
-ALOH: hypophosphatemia, osteodystrophy, constipation


-MGOH: diarrhea, loss of DTRs

-CACO3: hypercalcemia

-NAHCO3: Gas

Laxative drugs

-MgS04

-Bisacodyl

-Docusate

-Mineral oil

-Lactulose

-MgS04: water retention; increases intraluminal pressure

-Bisacodyl: direct intestinal wall stimulation

-Methylcellulose: bulk forming agent

-Docusate: detergent stool softener

-Mineral oil is a lubricant

-Lactulose is hyperosmotic

-Relief of constipation / diarrhea, normalization of bowel elimination



DRUGS THAT WORK ON SEROTONIN


-5HT is stored in the GI cells, neurons, and platelets

-All are g protein coupled except 5HT3 which is coupled directly to an ion channel

-XS 5HIAA is a marker for excess serotonin

Antiemetic

-Ondansetron and setrons

-Antagonist of 5HT3

-Decreases emesis in chemotherapy and radiation

-Cancer drug typically tested against is cisplatin

-This drug helps with cisplatin induced vomiting

Antiemetic

-H1 receptor antagonists

-Diphenhydramine

-Meclizine

-Promethazine

-Penetration of BBB and blocks input to vomiting center

-Decreases emesis

-Sedation

Drugs that act on 5HT receptors

-Sumatriptan

-Agonist at 5HT1d in cerebral vessles

-Decreases migraine pain

-Asthenia, chest pressure, throat pressure

Drugs that act on 5HT receptors

-Cyproheptadine

-Antagonist at 5HT2a receptors in CNS

-Used in carcinoid, GI tumors, post-gastrectomy

-Used in anorexia nervosa

-Marked H1 blocking action




Drugs that act of 5HT receptors

-Cisapride

-Receptor activator, works on 5HT4 receptor and is pro-kinetic

-Prokinetic in GERD

-Arrhythmia (restricted use drug)

Ergot alkaloids

-Ergotamine

-Methylsergide

-Partial AGONISM at alpha adrenorecptors and 5HT2 receptors in the vasculature.

-Vasoconstriction decreases pulsation in cerebral vessles

-Migraine attack

-Ergotamine: Acute relief

-Methylsergide: prophylaxis




NSAID drugs

-ASA

-irreversible COX inhibition

-COX1 and COX2 inhibition

-Inhibits thromboxane A2

-Higher doses have anti-inflammatory effect

-

-Antiplatelet activity

-Analgesia

-Anti-inflammatory

-Antipuretic

-High therapeutic doses involve mild uncoupling of oxidative phosphorylation. Increased respiration leads to respiratory alkalosis


-Metabolic acidosis can occur in toxic doses, hyperthermia, hypokalemia

-GI irritation

-Hypersensitivity

-SALICYLISM: tinnitus, vertigo, decreased hearing

-Exacerbation of asthma

-Increased PTT

-Increased bleeding time

-Zero order elimination at high doses

-Asthma, nasal polyps, rhinitis (forces arachnidonic acid down the lipooxygenase pathway

-Alkalinzation of urine to increase elimination of aspirin?

NSAID drugs

-Celecoxib

-Rofecoxib

-Reversible COX2 inhibition

-

-Pain

-Anti-inflammation

-Decreased GI effects

-Increase of PT with warfarin

-Cross allergenicity with sulfonamide (celecoxib)

-No effects on uric acid elimination

-Chronic use may cause renal or hepatic problems

NSAID drugs (other)

-ketorolac

-Indomethacin

-COX inhibition

-Pain

-Antiinflammation

-Toradol is effective atpain relief

-++ toxicity associated with indomethacin

NSAID drugs

-Acetaminophen

-Not a true NSAID

-No inhibition of COX in periphery, possible in CNS

-Relief of pain

-Antipyresis

-Toxicity

-Stores of glutathione are depleted in acetaminophen overdose. The reactive metabolite (N-acetylbenzoquinonemine) reacts with hepatocytes and causes N/V, abdominal pain, ultimately liver failure

-Antidote is administration of n-acetylcysteine within the first 12 hours

-No antiplatelet effects

-No GI distress

Disease modifying agents

-Hydoxychloroquine

-methotrexate

-Sulfasalazine

-Glucocorticoids

-Gold salts

-Penicillamine

-Etanercept

-Infliximab

-Leflunomide

-Used in initial management of RA

-Doses required generally result in marked advrse effects

-COX 2 drugs have found a place in management of RA

-These drugs modify the immune response involved

-Hydroxychloroquine: good for mild arthritis. Stabilizes lysosomes and decreases chemotaxis
-Methotrexate: cytotoxic to lymphocytes


-Etanercept: binds TNF, recombinant form of TNF receptor

-Infliximab: monoclonal Ab to TNF

-Management of RA

-GI distress, hemolysis in G6PDH

-Hematotoxicity, crystalluria

Antigout agents

-Colchicine

-Binds to tubulin, decreases microtubular polymerization, blocks leurkotrienes, decrease granulocyte migration

-Acute gout remediation

-Longer use can involve myelosuppression

-Gastritis

Antigout agents

-Allopurinol

-XO inhibitor

-Decreases purine metabolism

-Decreases uric acid

-Lower uric acid pool

-Chronic gout tx

-Inhibits 6-MCPT metabolism

Antigout agents

-Probenecid

-Inhibits proximal tubular reabsorption of urate

-Ineffective with low GFR

-Lowering of uric acid pool

-Chronic gout

-Probenecid inhibits the sewcretion of many acidic drugs including cephalosporins and f-quinolones

Antiinflammatory agents

-Glucocorticoids

-Dedcrease leukocyte migration

-Increase lysosomal membrane stability

-Increase capillary permeability

-Decrease cox 2 expressioin

-Antiinflammatory

-Immune suppression

-Sodium and h20 retention (aldosterone like effect)
-Immune suppression


-Increase glaucoma

-Aseptic necrosis

-Decrease wound healing

-Osteoporosis

-Decreased skeletal growth

Antiasthmatics / adrenergic agents

-Beta agonist

-Albuterol

-Salmeterol

-Beta selective drugs dilate bronchioles

-Short acting

-Salmeterol is longer acting, good for nocturnal asthma

-Relief of bronchospasm

-Acute asthmatic attack

-Tachycardia

-Sympathetic affects

Antiasthmatics / Muscarinic blocker

-Ipatroprim and other M blockers are anticholinergic

-Can cause bronchodilation in acute asthma


-Bronchospasm

-DOC caused by beta blockers

-Atropine like effects

-

Antiasthmatics

Methylxanthines

-Theophylline

-Inhibits phosphodiesterase

-Increases camp


-Adjunctive for asthma

-Many drug interactions

-Toxicity increased by erythromycin, cimetidine

Antiasthmatics

MAST cell stabilizers

-Cromolyn

-Nedocromil

-MAST cell membrane stabilizers

-Inhibit release of histamine

-Good for prophylaxis

-Minimal systemic toxicity

Antiasthmatics

Leukotriene inhibitors

-Zafirkulast

-Montekulast

-Zileuton

-Leukotriene receptor antagonists with a slow onset of activity

-Zileuton is a selective LOX inhibitor, decreasing formation of all LTs. More rapid onset

-Good for long term control

-Used prophylactically

-Headache, diarrhea, increased infections

-Adverse effects include asthenia, headache, and increased LFTs with zileuton

Antiasthmatics

-Budesomide

-Flunisolide

-Triamcinolone

-Steroid inhalers

-Good for prophylaxis

-Risk of candidiasis

Anticoagulants

-Heparins

-Danaproid

-Lovenox

-Mixture of sulfated polysaccharides with molecular weights of 15-20000 daltons

-LMWH have the advantage of longer half life, less thrombocytopena, enhanced factor

-Antithrombin III dependent

-Anticoagulant

-Used for thromboses, emboli, angina, DIC, open heart sx

-Monitor PTT

-Protamine is the chemical antagonist of heparin

-Toxicity involves bleeding., heparin induced thrombocytopenia

Anticoagulants

-Warfarin

-Lipid solible derivative of vitamin K

-Highly protein bound

-Decreases hepatic synthesis of vitamin K

-Vitamin K dependent factors are II, VII, IX, and X

-Coumarins prevent gamma carboxylation

-Anticoagulant

-Longer term anticoagulation for post MI, heart valve damage, atrial arrhythmias

-Bleeding, skin necrsis if low vitamin C

-Drug interactions include ASA, cimetidine, metrondiazole, phenytoin, sulfonamindes (Actions increased)
-Actions of warfarin are decreased by barbiturates, carbamazepine, cholestyramine, rifampin, thaizides


-The inducers of p450 will POTENTIATE warfarin activity

Thrombolytics

-Alteplase

-tPA is a natural activator, no allergy problems; fibrin specific

-Acts on fibrin bound fibrinogen

-CVA

-MI

-Bleeding

-IC bleeding

Thrombolytics

-Streptokinase

-Acts on bound and free plasminogen

-Bacterial protein

-MI


-Hypersensitivity

Antiplatelet agents

-Ticlopidine

-Clopidogrel

-Block ADP receptors, decreases platelet activation

-Alternatives to ASA in TIAs


-TIA

-post MI

-Unstable angina

-Hemorrhage

-Leukopenia

-TTP

Antiplatelt agents

-Abciximab

-GB IIb/IIIa inhibition

-Decreased aggregation by preventing cross linking

-Acute MI




Review of clotting cascade

-Platelets adhere to site of injury

-Activation by platelets by factors that include TXA2, adp, collagen, serotonin, increased IIb/IIIa expression

-Platelet aggregation occurs by a cross linking reaction due to fibrinogen binding to GB IIb/IIa

ENDOCRINE PHYSIOLOGY

Leuprolide

Naferelin

-Analogues of GnRH that will inhibit release of FSH/LH when given in steady doses


-Endometriosis

-Prostate carcinoma

-Agonists are given in steady doses and not pulsatile




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